Polyglutamic acid compositions and methods of use

Abstract

This document discloses compositions comprising one or more polyglutamic acid compounds. These compositions are used to treat, improve, prevent, or alleviate symptoms of vaginal dryness and menopausal symptoms. This document also describes compositions for treating, improving, preventing, or alleviating other dry skin symptoms on the body, extremities, hands, feet, neck, or face in subjects of all ages and sexes. This document also describes topical and suppository formulations of the compositions.

Description

Background Technology

[0001] Vaginal dryness is a common condition that affects women of all ages. However, it is most prevalent in postmenopausal women. Vaginal dryness in postmenopausal women may be related to declining estrogen levels. Topical estrogen therapy has been the most common treatment for vaginal dryness, but this therapy carries risks such as vaginal bleeding and an increased risk of uterine cancer. For patients who do not wish to or cannot consider estrogen therapy, hyaluronic acid is an alternative treatment. However, it also has side effects, including vulvovaginal candidiasis and bacterial vaginosis. Therefore, existing methods and compositions for treating vaginal dryness are insufficient, and this article provides solutions to help alleviate vaginal dryness.

[0002] Dry skin is another common condition that can affect women of all ages. It can also occur after menopause, or its frequency or severity may increase. In postmenopausal women, dry skin may be associated with declining estrogen levels.

[0003] Other symptoms of dry skin can affect people of all ages and genders. Summary of the Invention

[0004] Some embodiments of this disclosure relate to novel compositions containing one or more polyglutamic acid compounds and their use in treating and / or relieving symptoms of vaginal dryness and menopausal symptoms.

[0005] Some embodiments of this disclosure relate to novel compositions comprising one or more polyglutamic acid compounds, and their use in treating and / or improving symptoms of dry skin, such as menopausal dry skin. In some embodiments, the compositions comprising one or more polyglutamic acid compounds described herein are used to maintain healthy levels of dry skin, including maintaining healthy levels of dry skin compared to premenopausal levels.

[0006] Some embodiments of this disclosure relate to novel compositions comprising one or more polyglutamic acid compounds, and their use in treating and / or improving symptoms of dry skin, such as dry skin unrelated to menopause or decreased estrogen levels.

[0007] Some embodiments of this disclosure relate to novel compositions comprising one or more polyglutamic acid compounds, and their use in treating and / or improving other dry skin symptoms (e.g., other dry skin symptoms on the body, extremities, hands, feet, neck, or face) in people of all ages and sexes. In some embodiments, the compositions comprising one or more polyglutamic acid compounds described herein are used to maintain a healthy level of dry skin on the body, extremities, hands, feet, neck, or face of a subject.

[0008] These and other features, aspects, and advantages of this embodiment will be understood with reference to the following description and the appended claims. Detailed Implementation

[0009] This document describes compositions comprising one or more polyglutamic acid compounds and a pharmaceutically acceptable carrier. Each polyglutamic acid compound is prepared by reacting a glutamate monomer with a suitable initiator. The molecular weight of each polyglutamic acid compound is determined by the number of glutamate monomers linked to it, which corresponds to the n value described below.

[0010] The structure of the polyglutamic acid compound is shown below: n refers to the chain length of the polyglutamic acid compound, which can be from 300 to 30,000. The molecular weight of the polyglutamic acid compound disclosed herein can be from about 50 to 4,000 kDa. The compositions described herein may contain one or more polyglutamic acid compounds that can have different polymer chain lengths (i.e., different n values).

[0011] For example, but not limited to, the composition may comprise: a first polyglutamic acid compound, wherein the n value of the first polyglutamic acid compound is about 300 to 500; a second polyglutamic acid compound, wherein the n value of the second polyglutamic acid compound is about 1,000 to 10,000; and a third polyglutamic acid compound, wherein the n value of the third polyglutamic acid compound is about 20,000 to 30,000.

[0012] There is no particular limitation on the number of polyglutamic acid compounds with different n values ​​in the composition. In some embodiments, the composition may contain one, two, three, four, five, six or more different polyglutamic acid compounds with different n values.

[0013] Unbound by any specific theory, the compositions of this disclosure containing one or more polyglutamic acid compounds produce unexpectedly superior effects because these compounds can penetrate different layers of vaginal epithelial tissue according to specific proportions of polyglutamic acid compounds with different n values. For example, the composition may contain a first polyglutamic acid compound and a second polyglutamic acid compound, wherein the n value of the first polyglutamic acid compound is smaller than the n value of the second polyglutamic acid compound. It is believed that polyglutamic acid compounds with smaller n values ​​can penetrate deeper vaginal epithelial cells compared to polyglutamic acid compounds with larger n values. Furthermore, it is believed that the second polyglutamic acid compound, having an n value greater than that of the first polyglutamic acid compound, will not penetrate deeper into the epithelial layer; instead, the second polyglutamic acid compound will be closer to the surface than the first polyglutamic acid compound.

[0014] Some embodiments include a first polyglutamic acid compound, a second polyglutamic acid compound, and a third polyglutamic acid compound. In some embodiments, the first polyglutamic acid compound is a polyglutamic acid compound containing a greater number of glutamic acid monomers than the second polyglutamic acid compound. The second polyglutamic acid compound contains a greater number of glutamic acid monomers than the third polyglutamic acid compound. In some embodiments, the first polyglutamic acid compound is configured to penetrate into the stratum corneum of the subject's vaginal wall, the second polyglutamic acid compound is configured to penetrate into the granular layer of the subject's vaginal wall, and the third polyglutamic acid compound is configured to penetrate into the stratum spinosum of the subject's vaginal wall. In some embodiments, one or more polyglutamic acid compounds may have a sufficiently large n-value such that it does not penetrate any skin layer but remains on the skin surface and can act as a lubricant.

[0015] Additionally, or alternatively, and again without being bound by any specific theory, the present invention recognizes and discovers that the compositions of this disclosure comprising one or more polyglutamic acid compounds produce unexpectedly superior effects because these compounds are able to penetrate different layers of the subject's skin tissue, such as the epidermis and / or dermis of the subject's body, limbs, hands, feet, neck, or face, depending on a specific ratio of polyglutamic acid compounds with different n values. For example, the composition may comprise a first polyglutamic acid compound and a second polyglutamic acid compound, wherein the n value of the first polyglutamic acid compound is smaller than the n value of the second polyglutamic acid compound. It is believed that polyglutamic acid compounds with smaller n values ​​can penetrate deeper into the epidermis and / or dermis of the skin compared to polyglutamic acid compounds with larger n values. Furthermore, it is believed that the second polyglutamic acid compound, with an n value greater than that of the first polyglutamic acid compound, will not penetrate deeper into the epidermis and / or dermis of the skin; rather, the second polyglutamic acid compound will be closer to the surface than the first polyglutamic acid compound.

[0016] Other exemplary embodiments include a first polyglutamic acid compound, a second polyglutamic acid compound, a third polyglutamic acid compound, a fourth polyglutamic acid compound, and / or a fifth polyglutamic acid compound. In some embodiments, the first polyglutamic acid compound is a polyglutamic acid compound containing more glutamic acid monomers than the second polyglutamic acid compound. The second polyglutamic acid compound contains more glutamic acid monomers than the third polyglutamic acid compound. The third polyglutamic acid compound contains more glutamic acid monomers than the fourth polyglutamic acid compound. The fourth polyglutamic acid compound contains more glutamic acid monomers than the fifth polyglutamic acid compound.

[0017] In an exemplary embodiment, a first polyglutamic acid compound is configured to penetrate the epidermis, including the stratum corneum; a second polyglutamic acid compound is configured to penetrate the stratum lucidum; a third polyglutamic acid compound is configured to penetrate the stratum granulosum; a fourth polyglutamic acid compound is configured to penetrate the stratum spinosum; and / or a fifth polyglutamic acid compound is configured to penetrate the basal layer.

[0018] In an exemplary embodiment, a first polyglutamic acid compound is configured to penetrate into one of the following layers of the epidermis: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale; and a second polyglutamic acid compound is configured to penetrate into another layer of the epidermis: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.

[0019] In some implementations, one or more polyglutamic acid compounds may have a sufficiently large n value so that they do not penetrate any epidermal skin layer, but remain on the skin surface, such as the stratum corneum surface, and can act as a lubricant.

[0020] In other exemplary embodiments, the first polyglutamic acid compound is configured to penetrate into the epidermis, and the second polyglutamic acid compound is configured to penetrate into the dermis, such as the papillary dermis and / or the reticular dermis.

[0021] In another exemplary embodiment, a first polyglutamic acid compound is configured to penetrate into a first layer of the dermis, and a second polyglutamic acid compound is configured to penetrate into a second layer of the dermis.

[0022] There is no particular limitation on the amount of each polyglutamic acid compound in any composition described herein, which may be from about 10 μg to about 10 g.For example, the amount may be 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1.25 g, 1.5 g, 1.75 g, 2.0 g, 2.25 g, 2.5 g, 2.75 g, 3.0 g, 3.25 g, 3.5 g, 3.5 g, 3.75 g, 4.0 g, 4.25 g, 4.5 g, 4.75 g, 5.0 g, 5.25 g, 5.5 g, 5.75 g, 6.0 g, 6.25 g, 6.5 g, 6.75 g, 7.0 g, 7.25 g, 7.5 g, 7.75 g, 8.0 g, 8.25 g, 8.5 g, 8.75 g, 9.0 g, 8.25 g, 9.5 g, 9.75 g, 10 g or any amount therebetween.

[0023] The compositions disclosed herein can be used to treat, prevent, or relieve vaginal dryness, vaginal itching, and / or vaginal burning. In some embodiments, the compositions described herein can be used to maintain a healthy vaginal moisture level. In some embodiments, the compositions described herein can be used to accelerate wound healing, prevent urinary tract infections, and / or maintain the pH of vaginal tissue. In some embodiments, the compositions described herein are administered to a subject to avoid dyspareunia. In some embodiments, the compositions described herein are administered to a subject to revitalize vaginal tissue.

[0024] In some embodiments, the composition may be applied to the vaginal tissue of a subject to treat, prevent, relieve, and / or reduce symptoms of vaginal dryness. In some embodiments, the composition may be applied to the vaginal tissue of a subject to maintain a healthy level of vaginal moisture. In some embodiments, the composition may be applied to the vaginal tissue of a subject to treat, prevent, and / or relieve symptoms of vaginal dryness due to menopause. In some embodiments, the composition may be applied to the vaginal tissue of a subject to treat, prevent, and / or relieve one or more menopausal symptoms. In some embodiments, the composition may be applied to the vaginal tissue of a subject to reduce pain associated with sexual activity (including intercourse). In some embodiments, the composition may be applied to the vaginal tissue of a subject to treat, prevent, and / or relieve vaginal itching. In some embodiments, the composition may be applied to the vaginal tissue of a subject to treat, prevent, and / or relieve vaginal burning. In some embodiments, the composition may be used in one or more of the aforementioned situations.

[0025] Alternatively or additionally, the compositions disclosed herein may be used to treat, prevent, or improve dry, itchy, and / or burning skin in a subject, such as on the body, extremities, hands, feet, neck, and / or face. In some embodiments, the compositions described herein may be used to maintain healthy skin moisture levels. In some embodiments, the compositions described herein may be used to accelerate wound healing, prevent infection, and / or maintain the pH of skin tissue. In some embodiments, the compositions described herein are applied to a subject to revitalize skin tissue.

[0026] In some embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, extremities, hands, feet, neck, and / or face) to treat, prevent, improve, and / or alleviate symptoms of dry skin. In some embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, extremities, hands, feet, neck, and / or face) to maintain healthy moisture levels. In some embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, extremities, hands, feet, neck, and / or face) to treat, prevent, and / or improve symptoms of dry skin caused by menopause. In other embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, extremities, hands, feet, neck, and / or face) to treat, prevent, and / or improve other symptoms of dry skin in people of all ages and sexes, such as other symptoms of dry skin on the subject's body, extremities, hands, feet, neck, or face. In some embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, extremities, hands, feet, neck, and / or face) to treat, prevent, and / or improve pruritus. In some embodiments, the composition may be applied to the skin tissue of a subject (e.g., the subject's body, limbs, hands, feet, neck, and / or face) to treat, prevent, and / or improve skin burning. In some embodiments, the composition may be used in one or more of the above-described conditions.

[0027] In some embodiments, the composition may be applied to the subject's skin tissue (e.g., the subject's body, limbs, hands, feet, neck, and / or face) to form a barrier preventing moisture loss from the subject's skin and / or preventing dryness and irritation by locking moisture within the subject's skin. In some embodiments, the composition may be applied to the subject's skin tissue (e.g., the subject's body, limbs, hands, feet, neck, and / or face) to protect the subject's skin from environmental damage and / or to protect the subject's skin from allergens and infection-causing microorganisms (such as bacteria and fungi). In other embodiments, the composition may be applied to the subject's skin tissue (e.g., the subject's body, limbs, hands, feet, neck, and / or face) to promote anti-aging by keeping the subject's skin moist and supple.

[0028] In some embodiments, the compositions disclosed herein are in the form of pharmaceutically effective salts. The phrase "pharmaceutically acceptable salt" is recognized in the art and, as used herein, includes, but is not limited to, salts containing acidic or basic groups that may be present in the compositions disclosed herein. Compounds that are inherently basic are capable of forming a wide variety of salts with a variety of inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glycerates, glucuronides (gl... The compositions disclosed herein contain glycosidates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl) salts (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)carboxylic acid salts). In addition to the acids mentioned above, compounds containing an amino moiety present in the compositions disclosed herein can also form pharmaceutically acceptable salts with various amino acids. Compounds present in the compositions disclosed herein that are inherently acidic can form basic salts with various pharmaceutically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, silicon, phosphorus, and iron salts.

[0029] The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or solvents suitable for administering the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials for carrying or transporting a target drug agent from one organ or body site to another.

[0030] Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, glycerides, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginate; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. In one embodiment, a pharmaceutically acceptable carrier is suitable for intravenous administration. In another implementation, a pharmaceutically acceptable carrier is suitable for local injection.

[0031] The term "pharmaceutically acceptable ester" refers to the relatively non-toxic esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound or hydroxyl compound in its free acid form with a suitable esterifying agent. Carboxylic acids can be converted to esters by treatment with an alcohol in the presence of a catalyst. Hydroxyl compounds can be converted to esters by treatment with an esterifying agent such as an alkyl halide. The term also includes lower hydrocarbon groups capable of being solvated under physiological conditions, such as alkyl esters, methyl esters, ethyl esters, and propyl esters.

[0032] The dosage form of the compositions described herein is not particularly limited. In some embodiments, the compositions are formulated as topical dosage forms, such as creams or ointments. In some embodiments, the compositions are formulated as gels. In some embodiments, the compositions are formulated as suppositories.

[0033] In some embodiments, the suppository formulation comprises one or two polyglutamic acid compounds, a solubilizer, a humectant, a surfactant, and / or one or more suppository bases. The suppository formulation may also contain an emollient. An example of a solubilizer is water. An example of a humectant is glycerin. An example of a surfactant is polysorbate 80. Examples of suppository bases include PEG4000, Gelucire 43 / 01, PEG3350, Witepsol W-35®, and C12-C18 saturated fatty acid glycerides. An example of an emollient is Softisan 378. The molecular weight of the one or two polyglutamic acid compounds is from 50 kDa to 2000 kDa. For example, the molecular weight of the polyglutamic acid compound in the compositions disclosed herein can be 50 kDa, 100 kDa, 150 kDa, 200 kDa, 250 kDa, 300 kDa, 350 kDa, 400 kDa, 450 kDa, 500 kDa, 550 kDa, 600 kDa, 650 kDa, 700 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1000 kDa, 1050 kDa, 1100 kDa, 1150 kDa, 1200 kDa, 1250 kDa, 1300 kDa, 1350 kDa, 1400 kDa, 1450 kDa, 1500 kDa, 1550 kDa, 1600 kDa, 1650 kDa, 1700 kDa, 1750 kDa, 1800 kDa, etc. kDa, 1850 kDa, 1900 kDa, 1950 kDa, or 2000 kDa. There is no particular limitation on the weight percentage (% w / w) of each polyglutamic acid compound in any composition described herein, and it can be from about 0.01% to about 1%.For example, it could be 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%. %, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0. 51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%. 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1% or more, or any value between them. The weight percentage (%w / w) of the solubilizer, humectant, surfactant, one or more of the suppository base and emollient in the suppository formulation is not particularly limited, and may be 1% to 100%, about 0.1% to 11.4%, 0.1% to 1.4%, 0% to 100%, and 0% to 100%, respectively. The amounts of the polyglutamic acid compound, solubilizer, humectant, surfactant, suppository base and / or emollient are in synergistic ratios. As used herein, "synergistic ratio" refers to the ratio of unexpectedly superior pharmacological and physiological effects in subjects. A non-limiting example of a synergistic ratio of the amount of polyglutamic acid compound: solubilizer: humectant: surfactant: suppository base is 5:396:50:28:1521. A non-limiting example of a synergistic ratio of the amount of polyglutamic acid compound: solubilizer: humectant: surfactant to the amount of topical formulation is 5:396:50:28:1521.

[0034] In some embodiments, the suppository formulation contains only one polyglutamic acid compound. In some embodiments, the molecular weight of the compound is 100 kDa, 700 kDa, or 2000 kDa. In some embodiments, the suppository formulation contains a solubilizer, a humectant, a surfactant, and a suppository base. In some embodiments, the solubilizer is water, the humectant is glycerol, the surfactant is polysorbate 80, and the suppository base is a C12-C18 saturated fatty acid glyceride.

[0035] In some embodiments, the suppository formulation comprises two polyglutamic acid compounds. In some embodiments, the molecular weights of the compounds are 100 kDa and 700 kDa.

[0036] In some embodiments, the topical formulation comprises one or more polyglutamic acid compounds. Some embodiments of the topical formulation comprise a first polyglutamic acid compound and a second polyglutamic acid compound. In some embodiments, the first polyglutamic acid compound has a molecular weight of about 50–200 kDa. In some embodiments, the molecular weight of the first polyglutamic acid compound is in the range of about 50–100 kDa, 100–200 kDa, 50–150 kDa, 75–125 kDa, 50–125 kDa, 150–200 kDa, 100–175 kDa, and between. In some embodiments, the second polyglutamic acid compound has a molecular weight of about 500–900 kDa. In some embodiments, the molecular weight of the second polyglutamic acid compound is in the range of about 500–1000 kDa, 600–900 kDa, 700–900 kDa, 800–900 kDa, 500–600 kDa, 500–700 kDa, 500–800 kDa, 500–900 kDa, 700–800 kDa, 550–750 kDa, 650–850 kDa, and so on. In some embodiments, the topical formulation may comprise a first polyglutamic acid compound and a second polyglutamic acid compound, wherein the first polyglutamic acid compound has a molecular weight of about 100 kDa and the second polyglutamic acid compound has a molecular weight of about 700 kDa.

[0037] In some implementations, the suppository formulation may disintegrate within 5–10 minutes, 10–20 minutes, or 20–30 minutes. In some implementations, the suppository formulation may be used every two days, every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days, every ten days, every two weeks, monthly, or longer to provide rapid and lasting relief from vaginal dryness and menopausal symptoms.

[0038] In other embodiments, topical formulations (e.g., creams, ointments, or gels) may be applied multiple times daily, once daily, every two days, every three days, every four days, every five days, every six days, once weekly, every eight days, every nine days, every ten days, every two weeks, once monthly, or more frequently to provide rapid and lasting relief from menopausal-related dry skin symptoms and / or other dry skin symptoms in people of all ages and sexes, such as other dry skin symptoms on the subject's body, extremities, hands, feet, neck, or face. There are no particular limitations on the frequency of application of topical formulations. In some embodiments, topical formulations may be administered multiple times daily for several consecutive days without specific limitations. In some embodiments, the user may apply the topical formulation to the skin to prevent dry skin. In some embodiments, the user may apply the topical formulation to reduce the effects of dry skin and moisturize the skin. Topical formulations may be applied at a frequency that effectively maintains healthy skin moisture levels.

[0039] Although the invention has been described in detail for clarity and understanding purposes, it should be understood that various changes in form and detail may be made without departing from the true scope of the invention.

[0040] Example Example 1 In one embodiment, polyglutamic acid (Mw: 100 kDa; 5 mg; 0.25% w / w) was mixed with water (396 mg; 19.8% w / w), glycerol (50 mg; 2.5% w / w), polysorbate 80 (28 mg; 1.4% w / w), and C12-C18 saturated fatty acid glycerides (1521 mg; 76.04% w / w) to obtain a white suppository. Dissolution studies of the suppository were conducted using a phosphate buffer solution with a pH range of approximately 4.2–4.5, which falls within the normal vaginal pH range (3.8–5.0). The percentage of polyglutamic acid in the buffer solution was determined at 0.5 h, 0.75 h, 1 h, 2 h, 3 h, 6 h, 24 h, 30 h, and 48 h. The dissolution data are shown in Table 1 below.

[0041] Table 1: Dissolution Data

[0042] The suppositories were observed to completely disintegrate within 30 minutes. Data showed that 67% of the polyglutamic acid compound dissolved within 30 minutes, and the polyglutamic acid compound was completely dissolved in the buffer solution by the 3rd hour. Unexpectedly, stable dissolution was observed from the 0.5th hour to the 3rd hour. Also unexpectedly, 100% of the polyglutamic acid compound remained in the buffer solution at the 48th hour, indicating that the compound is stable in vaginal tissue and therefore can moisturize vaginal tissue for more than 2 days once applied. These unexpected results suggest that the composition can provide rapid and long-lasting relief from vaginal dryness symptoms.

[0043] Example 2 The vaginal suppository composition described in Example 1 above was studied to evaluate its short-term stability compared to the placebo prototype composition. The placebo composition was identical to the vaginal suppository composition except that it did not contain any polyglutamic acid compound. Both compositions were subjected to a 3-month ICH stability test at 2-8°C and 25°C / 60% relative humidity. At the end of the first and second months, the stability of the vaginal suppository composition was assessed by visual observation of appearance and the amount of residual polyglutamic acid compound in the composition. At the end of the third month, in addition to visual observation of appearance and the amount of residual polyglutamic acid in the composition, the stability of the vaginal suppository composition was assessed by the amount of dissolved polyglutamic acid compound. As for the placebo composition, its stability was assessed at the end of each month by visual observation of appearance and placebo interference.

[0044] Example 3 A test will be conducted using an in vitro vaginal tissue testing device to assess the activity and efficacy of polyglutamic acid compounds with different polymer chain lengths. Different polyglutamic acid compounds (i.e., those with different n-values) will be applied to the testing device, and the ability of these mixtures to penetrate the various tissue layers of the vaginal wall will be related to their n-value (i.e., the number of monomers in the polyglutamic acid compound) and their relative effect on vaginal moisture. Furthermore, compositions of polyglutamic acid compounds with different concentrations and different polymer chain lengths (i.e., different n-values) will be tested to determine their effects on vaginal moisture and penetration into the vaginal tissue layers.

[0045] Example 4 The effects of certain compositions described herein on the vaginal epithelium of a postmenopausal rat model will be tested.

[0046] Thirty female Wistar / Sprague rats (8 weeks old) were purchased from the Laboratory Animal Centre at Firat University. All rats were housed individually in a clean environment with controlled temperature, humidity, and light (12-hour light-dark cycle), and provided with free access to standard commercially available food and water. All experimental procedures followed guidelines established by the Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Firat University.

[0047] Rats with a regular estrous cycle of 4 days were selected for the experiment. As shown in Table 2, the rats were divided into 7 groups. After an acclimatization period, the rats underwent ovariectomy (OVX) or sham surgery (control) under anesthesia. An equal weight of adipose tissue was removed from the control group rats. Vaginal smears were evaluated daily post-surgery. Rats showing a regular estrous cycle of 4 days using only vaginal smears (before / after sham surgery / OVX) and showing constant white blood cell counts (after OVX) (n=10 per group) were included. The remaining rats were given a placebo (solvent) gel via vaginal or oral administration at the same dose as the composition received by the rats. Rats' body weight was measured weekly.

[0048] Table 2. Research Group

[0049] *Product dosage is converted using allometric scaling, which takes into account differences in body surface area. The equivalent dose for rats is calculated as follows, assuming a human weight of 60 kg: RD = HED(g) / 60kg * 6.17 (e.g., (50 mg / 60) * 6.17 = 5.14 mg / kg BW; where RD is the rat dose of the product, HED is the human equivalent dose of the product, and 6.17 is the conversion factor for converting the human dose to the rat dose).

[0050] On day 15, the therapeutic effect of each composition on vaginal atrophy was determined by histological examination of vaginal tissue obtained from vaginal smears from each rat. Vaginal smears were fixed and examined, and the expression of leukocyte esterase, β-glucuronidase, and coagulase was used to determine the effect of each composition on the vaginal microecological system. All rats were then sacrificed by cervical dislocation, and their vaginas and uteruses were removed. The wet weight of each uterus was determined after careful removal of any adhering tissue. To minimize anatomical variations, all uteruses were dissected at equal distances above the cervix. Vaginal tissue was then removed and sectioned into 1 mm × 1 mm × 2 mm sections, stained with 2.5% glutaraldehyde. A number of vaginal samples were taken and processed according to standard procedures for histological examination (4–5 μm sections stained with hematoxylin and eosin).

[0051] The repair capacity of each composition was assessed using Western blotting. Vaginal VEGF, p-AKT, COX-2, ER₂, and ER₃ were detected using Western blotting. In the Western blotting process, proteins were separated in a 10% polyacrylamide gel, electrotransferred to a polyvinylidene fluoride membrane, and the bands were blocked in 5% milk powder for 1 hour at room temperature and incubated with different primary antibodies (1:1000). Incubation was performed in PBS supplemented with 5% skim milk powder. After washing with Tris-buffered saline (TBS) containing 0.1% Tween-20 (TBS-T), the membrane was incubated for 1 hour at room temperature with an anti-rabbit IgG antibody conjugated with horseradish peroxidase. After washing with TBS-T, the antigen-antibody complexes were visualized using an enhanced chemiluminescence detection kit.

[0052] Example 5 An assay will be conducted using a skin tissue testing device to test the activity and efficacy of polyglutamate compounds with different polymer chain lengths. Different polyglutamate compounds (i.e., those with different n values) will be applied to the testing device, and their ability to penetrate various skin tissue layers will be correlated with their n value (i.e., the number of monomers in the polyglutamate compound) and their relative effect on skin moisture. Furthermore, compositions of polyglutamate compounds with different concentrations and different polymer chain lengths (i.e., different n values) will be tested to determine their effects on skin moisture and penetration into skin tissue layers.

Claims

1. A composition for treating dry skin, comprising one or more polyglutamic acid compounds and a pharmaceutically acceptable carrier.

2. The composition according to claim 1, wherein the one or more polyglutamic acid compounds comprise a first polyglutamic acid compound and a second polyglutamic acid compound.

3. The composition according to claim 2, further comprising a third polyglutamic acid compound.

4. The composition according to claim 3, further comprising a fourth polyglutamic acid compound.

5. The composition according to claim 4, further comprising a fifth polyglutamic acid compound.

6. The composition of claim 2, wherein the n value of the second polyglutamic acid compound is greater than the n value of the first polyglutamic acid compound, wherein the n value is the number of glutamic acid monomers linked together to form each polyglutamic acid compound.

7. The composition of claim 3, wherein the n value of the second polyglutamic acid compound is greater than the n value of the first polyglutamic acid compound, and the n value of the third polyglutamic acid compound is greater than the n value of the second polyglutamic acid compound, wherein the n value is the number of glutamic acid monomers linked together to form each polyglutamic acid compound.

8. The composition of claim 4, wherein the n value of the second polyglutamic acid compound is greater than the n value of the first polyglutamic acid compound, the n value of the third polyglutamic acid compound is greater than the n value of the second polyglutamic acid compound, and the n value of the fourth polyglutamic acid compound is greater than the n value of the third polyglutamic acid compound, wherein the n value is the number of glutamic acid monomers linked together to form each polyglutamic acid compound.

9. The composition of claim 5, wherein the n value of the second polyglutamic acid compound is greater than the n value of the first polyglutamic acid compound, the n value of the third polyglutamic acid compound is greater than the n value of the second polyglutamic acid compound, the n value of the fourth polyglutamic acid compound is greater than the n value of the third polyglutamic acid compound, and the n value of the fifth polyglutamic acid compound is greater than the n value of the fourth polyglutamic acid compound, wherein the n value is the number of glutamic acid monomers linked together to form each polyglutamic acid compound.

10. The composition according to claim 1, wherein the composition is a topical formulation.

11. The composition of claim 10, wherein the topical formulation is a cream.

12. The composition of claim 10, wherein the topical formulation is an ointment.

13. The composition of claim 10, wherein the topical formulation is a gel.

14. The composition according to claim 6, wherein the first polyglutamic acid compound has a molecular weight of 100 kDa and the second polyglutamic acid compound has a molecular weight of 700 kDa.

15. A method for treating dry skin, comprising applying the composition of claim 1 to the skin of a subject.

16. The method of claim 15, wherein the composition is applied to the body, limbs, hands, feet, neck and / or face of the subject.

17. The method of claim 16, wherein the composition is a topical formulation.

18. The method of claim 17, wherein the topical formulation is one of cream, ointment, and gel.

19. A method for maintaining a healthy level of skin hydration, comprising applying the composition of claim 1 to the skin tissue of a subject.

20. The method of claim 19, wherein the composition is applied to the body, limbs, hands, feet, neck and / or face of the subject.

21. The method of claim 20, wherein the composition is a topical formulation.

22. The method of claim 21, wherein the topical formulation is one of cream, ointment, and gel.

23. A method for treating, preventing, and / or improving one or more menopausal symptoms, comprising applying the composition of claim 1 to the skin tissue of a subject.

24. The method of claim 23, wherein the symptoms are dry skin, itchy skin, and / or burning skin.

25. The method of claim 24, wherein the composition is applied to the body, limbs, hands, feet, neck and / or face of the subject.

26. The method of claim 25, wherein the composition is a topical formulation.

27. The method of claim 25, wherein the topical formulation is one of cream, ointment, and gel.

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